Mtb regulators of essential and virulence-associated MmpLs

 描述(申请人提供)：尽管有抗生素可用于抗击结核病(TB)，但它是传染病导致死亡的主要原因之一。结核分枝杆菌(Mtb)是一种成功的病原体，因为它生存在免疫细胞内，并有效地建立和维持潜在的结核病感染。因此，了解建立或维持休眠的潜在机制可以为结核病治疗提供新的战略。分枝杆菌膜蛋白大蛋白(MMPL)是细胞壁脂类转运蛋白。这些转运蛋白与其附属的分枝杆菌膜蛋白小蛋白(MMPs)一起，在分枝杆菌的生理和发病机制中起着至关重要的作用。MmpL3是必需的；MmpL4、MmpL5、MmpL7、MmpL8、MmpL10和MmpL11对Mtb毒力有贡献。我们特别感兴趣的是MmpL3和MmpL11这两个运输霉菌酸脂的相关蛋白的功能。MmpL3转运海藻糖，是分枝杆菌复制和存活所必需的。我们发现MmpL11可以运输单链霉菌基二甘油和霉酚酸酯蜡。这些脂类有时被称为“储存脂类”，在体外与休眠细菌有关，并在结核病患者的肉芽肿中积聚。因此，MmpL11在临床上相关但知之甚少的结核分枝杆菌发病机制中发挥作用。虽然在识别MMPL底物方面已经取得了重大进展，但在不同环境条件下MMPL蛋白表达的调控及其在细胞壁重塑中的作用还没有被探索。拟议的研究将表征Mtb转录调节因子的结构和功能，该转录调节因子控制必要的和毒力相关的MMPL和MMPs蛋白的表达。我们的初步数据表明，脂肪酸直接调节某些转录因子的活性。这提出了一种模型，在该模型中，Mtb可以直接评估和响应脂肪酸中间体、代谢状态和营养可获得性，以控制MMPL和MMPs基因调控。通过定义MMPL转运体调控的分子机制并确定它们的调节子，我们将对主动分裂Mtb和潜伏或非复制的持久性Mtb之间的转换产生新的见解。

 DESCRIPTION (provided by applicant): Despite the availability of antibiotics to combat Tuberculosis (TB), it is one of the leading causes of death due to infectious disease. Mycobacterium tuberculosis (Mtb) is a successful pathogen because it survives within immune cells and effectively establishes and maintains a latent TB infection. Therefore, understanding the mechanisms underlying the establishment or maintenance of dormancy can inform new strategies for TB therapeutics. Mycobacterial membrane protein large (MmpL) proteins are dedicated cell wall lipid transporters. Along with their accessory Mycobacterial membrane protein small (MmpS) proteins, these transporters are crucial players in mycobacterial physiology and pathogenesis. MmpL3 is essential; and MmpL4, MmpL5, MmpL7, MmpL8, MmpL10 and MmpL11 contribute to Mtb virulence. The function of the related proteins MmpL3 and MmpL11 that transport mycolic acid-containing lipids are of particular interest to us. MmpL3 transports trehalose monomycolate and is required for mycobacterial replication and viability. We showed that MmpL11 transports monomeromycolyl diacylglycerol and a mycolate ester wax. These are species of lipids that are sometimes referred to as "storage lipids" and are associated with dormant bacteria in vitro and accumulate in granulomas of TB patients. Therefore, it appears that MmpL11 plays a role in a clinically relevant, but poorly understood, aspect of Mtb pathogenesis. While significant advances have been made identifying MmpL substrates, the regulation of MmpL protein expression and their role in cell wall remodeling in different environmental conditions has not been explored. The proposed studies will characterize the structure and function of Mtb transcriptional regulators that control expression of essential and virulence-associated MmpL and MmpS proteins. Our preliminary data indicate that fatty acids directly modulate activity of some transcription factors. This suggests a model where Mtb can directly assess and respond to fatty acid intermediates, metabolic state and nutrient availability to control mmpL and mmpS gene regulation. By defining the molecular mechanisms underlying the regulation of MmpL transporters and identifying their regulons, we will generate novel insights into the transition between actively dividing Mtb and latent or non-replicating persistent Mtb.